Abstract Priorities for improving infant HIV-free survival in the developing world include preventing late mother-to-child HIV transmission (MTCT) during breastfeeding (BF) and reducing infant mortality after weaning. We hypothesize that cotrimoxazole (CTX) prophylaxis may reduce mortality among HIV-exposed but uninfected infants, particularly early in life for formula fed (FF) infants and after weaning in BF infants. CTX may therefore allow feeding strategies that reduce the period of BF and minimize MTCT risk. The proposed study is a randomized, double-blinded, placebo-controlled trial among 3,308 mother/infant pairs. The trial will compare survival (and HIV-free survival) at 12 months among infants receiving CTX vs. placebo from 4 weeks through 12 months. Feeding strategy will be observational, and the CTX vs. placebo randomization will be balanced across feeding methods. Supported feeding options will include exclusive BF + infant nevirapine prophylaxis for up to 3 months, exclusive BF + maternal HAART (if available) for up to 6 months, or FF from birth. The primary endpoint will be survival at 12 months by CTX or placebo arm. Secondary endpoints will evaluate survival and morbidity/mortality at 18 months; safety of CTX prophylaxis; survival (and HIV-free survival) between CTX/placebo arms by feeding method; MTCT by chosen feeding method at 1, 3, 6, and 12 months; survival with early vs. later weaning; and an analysis of maternal characteristics as predictors for feeding choice and HIV-free survival. All mothers and infants will receive antenatal and peripartum standard of care prophylaxis from the Botswana Government to prevent MTCT. HAART and CTX will be available from the Botswana Government for all qualifying HIV-infected women and infants. PUBLIC HEALTH RELEVANCE: The competing risks of increased mortality from formula feeding and HIV transmission from breastfeeding remain one of the central dilemmas for early childhood survival in HIV-affected regions of the developing world. We hypothesize that in developing regions where formula feeding or early weaning are already common, the ideal balance for reducing both mother-to-child HIV transmission and infant mortality during infancy may be a short period of breastfeeding with infant nevirapine prophylaxis followed by formula feeding and infant prophylaxis with cotrimoxazole. If proven effective, these simple interventions -- used in the novel manner proposed in this randomized study -- could be combined to optimize HIV-free infant survival throughout much of the developing world.